Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

Summary: Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis u...

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Autores principales:	Zhiqiang Li, Yeun-po Chiang, Mulin He, Tilla S. Worgall, Hongwen Zhou, Xian-Cheng Jiang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Genetics Molecular genetics Omics Science Q
Acceso en línea:	https://doaj.org/article/c1534ea8bb3b4764a344f509814da050
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spelling	oai:doaj.org-article:c1534ea8bb3b4764a344f509814da0502021-12-04T04:35:31ZLiver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation2589-004210.1016/j.isci.2021.103449https://doaj.org/article/c1534ea8bb3b4764a344f509814da0502021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221014206https://doaj.org/toc/2589-0042Summary: Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis.Zhiqiang LiYeun-po ChiangMulin HeTilla S. WorgallHongwen ZhouXian-Cheng JiangElsevierarticleGeneticsMolecular geneticsOmicsScienceQENiScience, Vol 24, Iss 12, Pp 103449- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics Molecular genetics Omics Science Q
spellingShingle	Genetics Molecular genetics Omics Science Q Zhiqiang Li Yeun-po Chiang Mulin He Tilla S. Worgall Hongwen Zhou Xian-Cheng Jiang Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
description	Summary: Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis.
format	article
author	Zhiqiang Li Yeun-po Chiang Mulin He Tilla S. Worgall Hongwen Zhou Xian-Cheng Jiang
author_facet	Zhiqiang Li Yeun-po Chiang Mulin He Tilla S. Worgall Hongwen Zhou Xian-Cheng Jiang
author_sort	Zhiqiang Li
title	Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_short	Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_full	Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_fullStr	Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_full_unstemmed	Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation
title_sort	liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: an effect of glucosylceramide accumulation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/c1534ea8bb3b4764a344f509814da050
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Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

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